[unreadable] [unreadable] Curcumin, a pigment in turmeric, possesses anti-inflammatory, antioxidant, antitumor, neuroprotective, and immunomodulatory activities. It exerts striking inhibitory effects on diverse cellular events associated with tumor initiation, promotion, and progression, thus holds great promise for development as a chemopreventive agent for prostate cancer. The rationale for using curcumin as a chemopreventive agent comes from the epidemiological studies and our preliminary data. Curcumin induces apoptosis through engagement of both mitochondrial and death receptor pathways of apoptosis. Furthermore, curcumin, although effective alone, can sensitize prostate cancer cells to TRAIL. However, the mechanisms by which curcumin induces sensitivity in prostate cancer cells are not known. Studies proposed in this application will not only fill this gap in our knowledge but also generate data that will guide us in formulating curcumin and TRAIL-based strategies for prevention and/or treatment of human prostate cancers. Based on our preliminary findings, we hypothesize that curcumin will be highly effective in suppressing growth of human prostate cancer cells due to its ability to induce apoptosis through upregulation of death receptors and proapoptotic members of Bcl-2 family and activation of caspase(s). We propose to test this hypothesis by: (1) Determining the molecular mechanisms by which curcumin inhibits proliferation and induces apoptosis in human prostate cancer cells, and (2) Determining the effects of curcumin and/or TRAIL on growth of human prostate cancer cells orthotopically implanted in nude mice. In Specific Aim 2, tumors from the vehicle treated control and curcumin and/or TRAIL treated mice will be examined to determine the extent to which curcumin and/or TRAIL-induced molecular changes pertaining to apoptosis induction observed in cultured cells (Specific Aim 1) correlate with their effects in vivo. Specifically, studies are designed to determine the contribution of mitochondrial and/or death receptor pathways in curcumin-induced apoptosis. In summary, the studies proposed in this application will define the mechanism by which curcumin inhibits growth of human prostate cancer cells and determine in vivo efficacy of curcumin and/or TRAIL against prostate cancer using an animal model, which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancer. We expect the proposed studies to yield data in support of our hypothesis and to serve as a critical step in developing new approaches to prostate cancer prevention. [unreadable] [unreadable] [unreadable]